Studies of pharmacokinetic and pharmacodynamic properties of isoallopregnanolone in healthy women.
BACKGROUND
The pharmacokinetics and behavioral effects of isoallopregnanolone (3beta-hydoxy-5alpha-pregnan-20-one) in women are not known.


OBJECTIVE
Allopregnanolone (3alpha-hydoxy-5alpha-pregnan-20-one) is a well-known neurosteroid, acting via the GABA(A) receptor in the human brain. The naturally occurring progesterone metabolite isoallopregnanolone is the 3beta-stereoisomer of allopregnanolone. Prior studies have concluded that isoallopregnanolone has no effect on the GABA(A) receptor. However, an antagonistic effect of isoallopregnanolone to allopregnanolone on the GABA(A) receptor has been shown in animal and in vitro studies. The purpose of this study was to evaluate the pharmacokinetics and behavioral effects of isoallopregnanolone in humans.


METHODS
Six healthy women were given three increasing doses of isoallopregnanolone intravenously in the follicular phase. Repeated blood samples for analyses of isoallopregnanolone and allopregnanolone concentrations were drawn. Saccadic eye movement variables, self-rated sedation, and mood rating scales were used during the test day. A Likert scale for prospective symptoms was used to measure daily fluctuations during the ongoing menstrual cycle.


RESULTS
Exogenously administered isoallopregnanolone produced a dose-dependent increase in the serum concentration of isoallopregnanolone. In parallel, there was also a rise in the allopregnanolone concentration. There was a decrease in saccadic eye movement variables, but no effect was found on self-rated sedation or mood and no changes were seen in prospective symptoms during the menstrual cycle.


CONCLUSIONS
After administration of isoallopregnanolone at a cumulative dose of 0.20 mg/kg, no adverse effects were observed. There is a metabolism of isoallopregnanolone to allopregnanolone, most likely explaining the effects on the saccadic eye movements.
Hedström
Helena
H
Umeå Neurosteroid Research Center, Department of Clinical Science, Obstetrics, and Gynecology, Umeå University, Umeå, Sweden.
Bixo
Marie
M
Nyberg
Sigrid
S
Spigset
Olav
O
Zingmark
Elisabeth
E
Bäckström
Torbjörn
T
D000328:Adult; D000339:Affect / Q000187:drug effects*; D001711:Biotransformation; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008597:Menstrual Cycle; D011280:Pregnanolone / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D012438:Saccades / Q000187:drug effects*; D013237:Stereoisomerism; D014851:Wakefulness / Q000187:drug effects*; D055815:Young Adult
D011280:Pregnanolone